Age-related macular degeneration (ARMD) is the most important cause of lost central vision in the elderly. Although ARMD pathogenesis is unknown, oxidant injury to the RPE has been implicated as a mechanism. Since oxidant-mediated cellular injury leads to dysregulation of extracellular matrix (ECM) turnover by injured cells in many age-related degenerative disorders, this may also be the case for injured RPE. Additionally, dysregulated MMP-2 and its major substrate type IV collagen, may be induced in injured RPE to promote ARMD progression by macrophage-derived oxidants, myeloperoxidase (MPO), as well as macrophage-derived cytokines, especially tumor necrosis factor-alpha (TNF-alpha). Alternatively, estrogens, which are natural antioxidants and modulators of the molecules involved in ECM turnover, might oppose the injurious effects of macrophage-derived oxidants and cytokines on RPE production of MMP-2 or collagen. Based on preliminary data, we postulate that macrophage-derived MPO injures the RPE cell membrane to induce bleb formation but with simultaneous down-regulation of MMP-2 (leading to trapping of the blebs as subRPE BLD). Subsequent RPE exposure to macrophage-derived TNF-alpha, during a vulnerable post-blebbing period, will stimulate increased MMP-2 and collagen expression. Conversely, we expect that estrogen's antioxidant action on the cell membrane will diminish MPO-induced blebbing and that activation of estrogen receptors will modify matrix molecule dysregulation.